Favorable survival and tolerability of the GMALL protocol in adolescents and young adults with ALL: A single-center experience

Abstract

Abstract Background: Treatment of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) using pediatric-inspired protocols has been associated with improved outcomes. In general, pediatric and pediatric-inspired regimens involve high cumulative doses of vincristine, glucocorticoids, and asparaginase (ASP), with most regimens adding an anthracycline (usually doxorubicin or daunorubicin), along with intensive and prolonged central nervous system prophylaxis. However, most evidence supporting these approaches originates from clinical trials. This report presents real-world experience with a pediatric-inspired regimen, The German Multicenter Study Group (GMALL) protocol, in the treatment of ALL in the AYA population, based on a cohort of patients managed at a national tertiary referral center. Aims: We aimed to assess the efficacy of the GMALL protocol, specifically versions 07/03 and 08/13, administered between 2016 and 2024 to all newly diagnosed patients aged 18 to 40 diagnosed with Ph-negative ALL. Methods: This is a single-center retrospective cohort study conducted in Israel. Demographic, clinical, and treatment-related data from consecutive patients were collected. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan–Meier method; differences between groups were compared via log-rank tests, with hazard ratios and 95% confidence intervals (CI) reported; a Pvalue < 0.05 was considered statistically significant. Results: Thirty-eight patients aged 18–40 years (median age 24) with Philadelphia chromosome–negative ALL were treated at our center, with a median follow-up of 36 months (range, 6–102). Sixty-six percent were male; 42% had B-lineage and 58% had T-cell phenotype. Fourteen patients were classified as high-risk (HR) and 24 as standard-risk (SR) per the protocol criteria. Ten patients had a BMI greater than 25. Only one patient had primary CNS involvement at diagnosis. Four patients (10%) were CD20 positive, and three of them received rituximab (3-7 doses in total). Five received blinatumomab prior to transplant for MRD eradication, and 16 underwent allogeneic transplantation in first complete remission (CR1). Adherence to the GMALL protocol was high, with a dropout rate of 8%. Morphological remission rate post induction was 92%. Complete molecular remission (CMR) rate at week 12 (end of consolidation 1) was 63%. Three-year EFS was 65%, 78% and 42% for the overall cohort, SR and HR (95% CI, 47-83, 60-96, 11-73). Overall, 3-year OS was 73%, 78% and 63% for all patients, SR and HR, respectively (95% CI, 57-89, 58–98, 34-92); Patients achieving CMR by week 12 had a 3-year OS of 93%, compared to 32% (95% CI, 2–61) in those who did not. The regimen was well tolerated. Death rate during induction was 0%. Dose reductions or delays due to treatment-related adverse events (TRAEs) were infrequent. Of note, four patients experienced grade 3–4 PEG-asparaginase–related toxicities: acute pancreatitis (n=2), anaphylaxis (n=1), and transaminitis (n=1). Conclusion: Our single-center experience in AYA-ALL patients aged 18–40 treated with the pediatric- inspired GMALL protocol demonstrates favorable survival outcomes and good tolerability. These real-world findings align with previously reported GMALL clinical trial data and are comparable to outcomes seen with more intensive pediatric regimens in this age group.